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(Circulation. 2007;115:493-500.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Nuno M.M. Pires, MSc^*; Thijs W.H. Pols, MSc^*; Margreet R. de Vries, BSc; Claudia M. van Tiel, PhD; Peter I. Bonta, MD; Mariska Vos, BSc; E. Karin Arkenbout, MD, PhD; Hans Pannekoek, PhD; J. Wouter Jukema, MD, PhD; Paul H.A. Quax, PhD; Carlie J.M. de Vries, PhD

From the Gaubius Laboratory, TNO–Quality of Life (N.M.M.P., M.R.d.V., P.H.A.Q.), Leiden; the Departments of Cardiology (N.M.M.P., J.W.J.) and Surgery (P.H.A.Q.), Leiden University Medical Center, Leiden; and the Department of Medical Biochemistry (T.W.H.P., C.M.v.T., P.I.B., M.V., E.K.A., H.P., C.J.M.d.V.), Academic Medical Center, Amsterdam, the Netherlands.

Correspondence to Dr Carlie J.M. de Vries, Department of Medical Biochemistry, Academic Medical Center, K1-116, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. E-mail c.j.devries{at}amc.uva.nl

Received March 14, 2006; accepted November 27, 2006.

Background— Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77.

Methods and Results— It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [³H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27^Kip1 in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors.

Conclusions— Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis.

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